A remarkable change in inhibition potency and selectivity of isofagomine by simple N-modification

Monatshefte für Chemie / Chemical Monthly Pub Date : 2024-05-29 DOI:10.1007/s00706-024-03210-7

André Culum, Herwig Prasch, Tobias Dorn, Roland Fischer, Ema Gardić, Franziska Schmutz, Magdalena Steinbrugger, Arnold E. Stütz, Patrick Weber, Tanja M. Wrodnigg, Martin Thonhofer

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Abstract

Herein, we present an alternative and elegant synthetic approach toward powerful β-glucosidase inhibitor isofagomine. Derivatizations of the ring nitrogen provided a selected set of N-modified isofagomine analogues. Biological evaluation of these compounds showed a remarkable change in potency as well as α/β-preference for various glycosidases from different sources when compared to the parent compound isofagomine. Overall, the conducted N-modification improved the potency against α-glucosidase from Saccharomyces cerevisiae (GH13). Coming along, significant diminished activities toward GH1 family β-glucosidases from three different sources have been observed for all tested derivatives. Moreover, and contrary to isofagomine, deactivations of β-galactosidase from Escherichia coli (GH2) as well as α-mannosidase from Canavalia ensiformis (GH38) have not been verified for this series of compounds.

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通过简单的 N-修饰，异法哥明的抑制效力和选择性发生了显著变化

在此，我们提出了一种替代性的、优雅的合成方法，以获得强效的β-葡萄糖苷酶抑制剂异法哥明。环氮的衍生化提供了一组精选的 N-修饰异法哥明类似物。对这些化合物进行的生物学评估显示，与母体化合物异法哥明相比，它们对不同来源的各种糖苷酶的效力和 α/β 偏好都发生了显著变化。总体而言，N-修饰提高了对来自酿酒酵母（GH13）的α-葡萄糖苷酶的效力。此外，还观察到所有测试衍生物对来自三种不同来源的 GH1 家族 β-葡萄糖苷酶的活性明显降低。此外，与异法哥明相反，这一系列化合物对大肠杆菌的 β-半乳糖苷酶（GH2）和罐头虫的α-甘露糖苷酶（GH38）的失活作用尚未得到验证。

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Monatshefte für Chemie / Chemical Monthly

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